1. Field of the Invention
The invention relates generally to the fields of autoimmunity and inflammatory bowel disease and more specifically to the development of pouchitis in patients with ulcerative colitis.
2. Background Information
Inflammatory bowel disease (IBD) is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn""s disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, abdominal pain, and fever the three most common presenting symptoms. The diarrhea may range from mild to severe and in ulcerative colitis often is accompanied by bleeding. Anemia and weight loss are additional common signs of IBD. Ten percent to fifteen percent of all patients with IBD will require surgery over a ten year period. In addition, patients with IBD are at increased risk for the development of intestinal cancer. Reports of an increasing occurrence of psychological problems, including anxiety and depression, are perhaps not surprising symptoms of what is often a debilitating disease that strikes people in the prime of life.
Progress has been made in diagnosing IBD and in distinguishing, in many cases, Crohn""s disease from ulcerative colitis. However, Crohn""s disease and ulcerative colitis each can represent a collection of heterogeneous disease types that affect the gastrointestinal tract and produce similar symptoms. One aspect of the heterogeneity associated with inflammatory bowel disease is revealed by the stark contrast in outcomes seen following colectomy for treatment of uncontrolled ulcerative colitis. The preferred procedure is abdominal colectomy with ileal pouch anal anastomosis (IPAA), whereby the diseased colonic mucosa is removed while continence is maintained through creation of an ileal reservoir or xe2x80x9cpouch.xe2x80x9d Although a subgroup of ulcerative colitis patients experience a favorable outcome following surgery, in the ten years after surgery almost 50% develop xe2x80x9cpouchitis,xe2x80x9d an inflammation of the pouch that can mimic the original symptoms of ulcerative colitis. In some patients, the recurrent symptoms of pouchitis are as debilitating as the symptoms present prior to surgery. Thus, for those who suffer from recurrent or xe2x80x9cchronicxe2x80x9d pouchitis, surgical treatment of ulcerative colitis provides little or no therapeutic value.
A genetic method of determining the subgroup of ulcerative colitis patients at increased risk for development of pouchitis or chronic pouchitis would be useful in the medical management of these patients following surgery and in identifying good candidates for surgical treatment. Unfortunately, a genetic method for predicting the development of pouchitis or chronic pouchitis currently is not available. Thus, there is a need for a convenient and non-invasive genetic method of determining the risk of developing pouchitis or chronic pouchitis following pouch surgery. The present invention satisfies this need and provides related advantages as well.
The present invention provides a method of determining a risk of pouchitis development following a surgical procedure where an internal pouch is created in a patient with ulcerative colitis. The method is practiced by determining in the patient the presence or absence of a pouchitis-associated allele linked to an interferon xcex3 receptor locus, where the presence of the pouchitis-associated allele indicates an increased risk of pouchitis development. The interferon xcex3 receptor locus to which the pouchitis-associated allele is linked can be, for example, an interferon xcex3 receptor 1 gene. A pouchitis-associated allele useful in the invention can be, for example, an allele located within the sixth intron of the interferon xcex3 receptor 1 gene, such as the FA1 microsatellite 171 allele. In one embodiment, the pouchitis-associated allele is associated with chronic pouchitis with an odds ratio of at least 4 and a lower 95% confidence limit greater than 1. The methods of the invention can be useful in identifying good candidates for surgical treatment of ulcerative colitis and in the selective medical management of high risk patients following surgery, as described further below.
In a preferred embodiment, the invention provides a method of determining a risk of chronic pouchitis development following ileal pouch anal anastomosis in a patient with ulcerative colitis. In this method, one determines the presence or absence of an interferon xcex3 receptor 1 FA1 microsatellite 171 allele in the patient, and the presence of the 171 allele indicates an increased risk of chronic pouchitis development.
In another embodiment, a method of the invention for determining a risk of pouchitis development in a patient with ulcerative colitis is practiced by obtaining from the patient material which contains nucleic acid including the FA1 microsatellite locus of the interferon xcex3 receptor 1 gene; and enzymatically amplifying the nucleic acid to produce an amplified fragment containing the FA1 microsatellite locus, where the presence of the FA1 microsatellite 171 allele indicates an increased risk of pouchitis development. If desired, one can further include a step of electrophoresing the amplified fragment to determine whether a FA1 microsatellite 171 allele is present.